Title Page
Contents
LIST OF ABBREVIAIONS 10
ABSTRACT 11
I. INTRODUCTION 14
II. MATERIALS AND METHODS 17
1. Cell culture and cell line establishment 17
2. Mutagenesis and cloning 18
3. Co-immunoprecipitation 18
4. siRNA transfection 19
5. Immunoblotting 19
6. Cell cycle analysis 20
7. Cell proliferation assay 21
8. Sensitivity assay 21
9. Survival analysis 22
10. Immunofluorescence 22
11. Peptides 23
12. Antibodies 23
III. RESULTS 25
1. The ANK domain of TONSL directly interacts with histone H3-H4 complex 25
2. Defect in TONSL-histone interaction leads to hyper-phosphorylation of CHK1 and CHK2 and cell cycle arrest 30
3. TONSL-histone interaction is critical for cell proliferation and repairing DNA damage induced by CPT 35
4. TONSL-histone interaction plays an important role in cell survival in patient-derived dermal fibroblasts presented with SPONASTRIME dysplasia 38
5. Enhanced expression of TONSL shows poor survival in various cancer patients 43
6. Pilot study of chemotherapeutics development by inhibition of TONSL-histone interaction 50
7. Development of anti-cancer peptides targeting TONSL-histone interaction 57
IV. DISCUSSION 62
V. REFERENCES 65
ABSTRACT IN KOREAN 71
Figure 1. Establishment of cell-based assays using HeLa cells stably... 29
Figure 2. Hyperactivated DNA damage responses in cells that defects... 34
Figure 3. Analysis of cell proliferation and CPT sensitivity with stable... 37
Figure 4. Analysis of DNA damage responses in patient-derived dermal... 42
Figure 5. Kaplan-Meier analysis of overall survival for various cancer patients 46
Figure 6. Targeting TONSL-histone interaction in cisplatin-resistant cells 49
Figure 7. Pilot study of chemotherapeutics development by inhibition of... 56
Figure 8. Development of anti-cancer peptides targeting TONSL-... 61